TNFα is an inflammatory cytokine produced by cells in response to infection or disease. TNFα induces a wide range of effects in different cell types, including induction of the inflammation, inhibition of viral replication and cell death via either apoptosis or necrosis. TNFα-induced inflammation is implicated in the etiology of many diseases including, but not limited to, rheumatoid arthritis, Crohn's disease, psoriasis and Alzheimer's disease.
CD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily which is constitutively or inducibly expressed on the surface of a variety of immune and non-immune cell types, including B cells, macrophages, dendritic cells, microglia, endothelial cells, epithelial cells, and keratinocytes. The CD40 ligand, CD154, is transiently expressed on the surface of activated helper CD4+ T cells. The binding of CD154 to CD40 on the surface of antigen presenting cells contributes to the activation of such immune cells and induces a number of downstream effects, including the production of TNFα.
Macrophages are major producers of TNFα under inflammatory conditions.
Macrophages originate from bone marrow-derived mature monocytes. In response to cytokines, myeloid progenitor cells in the bone marrow differentiate into monocytes, which then enter into the blood stream. In response to chemokine signaling or tissue insult, monocytes rapidly migrate into different tissues where they differentiate into tissue macrophages under the influence of growth factors such as G-MCSF or MCSF.
As described above, monocytes and macrophages are activated through contact with activated T cells. The interaction of CD40 on monocytes and macrophages with CD154 on activated CD4+ T cells is essential for T cell-mediated macrophage activation and the resultant production of TNFα. Activated T cells therefore activate resting monocytes and macrophages via CD40 ligation in a contact-dependent manner at sites of inflammation. The consequence of this interaction is the maintenance and augmentation of the inflammatory process that includes the activation of macrophages, increased production of inflammatory cytokines and enhanced monocyte viability.
There is therefore great need for novel compositions and methods that inhibit the production of TNFα downstream of CD40 activation. Such compositions and methods are useful, for example, in the treatment of inflammatory diseases associated with TNFα production and/or CD40 activation.